Despite dramatic advances in HIV-1 prevention modalities and increased global access to effective combination antiretroviral therapy (cART), new HIV-1 infections continue to occur at an alarming rate. Thus despite the promise of cART, an effective vaccine against HIV-1 is clearly needed to end the epidemic (Fauci et al., 2014). Despite the ability of broadly neutralizing antibodies to be induced in natural infection (Scheid et al., 2011; Walker et al., 2011 b; Walker et al., 2009), it is still unclear how to induce these, and there is a growing consensus that an effective vaccine will require induction of neutralizing antibodies, CD4 T cell responses, and CDS T cell responses (Fauci and Marston, 2014; Walker et al., 2011 a). A precise understanding of the antiviral properties of adaptive T cell responses is thus critical, but is only beginning to be understood. Key to understanding these antiviral properties is detailed examination of the function and evolutionary fate of these responses from the time of transmission, as well as an understanding of how pre-infection immune status impacts the ability of adaptive T cell immune responses to control viremia. During the past funding period of this R37 we have established a unique cohort of persons in whom we have pre-infection samples as well as samples from onset of viremia through to viral set point, which is now allowing us to define viral and host immunologic dynamics prior to and during the peak of viremia. We will continue to pursue the specific aims as outlined in the original submission, building on the substantial progress we have made during the first three years of funding.